phorbol-12-13-didecanoate and phorbol-12-13-diacetate

The effects of TPA, PDD, PDB, PDA, or MEZ on epithelial and mesenchymal skin tumors induced by a s.c. injection of MCA were studied histologically. Group-I mice received only MCA. At 6 weeks after MCA injection, mice in groups II to VII received acetone, 1.8 nmol TPA, PDD, PDB, PDA, or 6.1 nmol MEZ respectively in 0.1 ml acetone twice weekly until tumor development. Alterations in skin tumor induction patterns were also studied in animals that had been exposed to TPA or acetone for 10 weeks prior to s.c. injection of MCA. Exposure of mouse skin to TPA before or after carcinogen administration increased 2- to 3.5-fold, the incidence of carcinoma and mixed tumors of epithelial and mesenchymal histogenesis. The average time of tumor induction decreased in mice treated with MCA + TPA and 100% of the test animals in the TPA + MCA group developed tumors. In contrast, TPA-related phorbol esters inhibited skin tumor development, particularly trichoepithelioma and fibrosarcoma and increased the average time of tumor induction.

Topics: Animals; Carcinoma; Diterpenes; Female; Mesenchymoma; Methylcholanthrene; Mice; Mice, Inbred Strains; Phorbol Esters; Skin Neoplasms; Terpenes; Tetradecanoylphorbol Acetate

The effect of tumor promoter phorbol esters on cell proliferation was investigated in human breast cancer cell line MCF-7. During a 4-day culture period, the various phorbol ester derivatives TPA, PDD, PDBu, PDBz and PDA inhibited the proliferation of MCF-7 cells in a dose-dependent manner, with respective IC50 of 0.06, 0.75, 2.4, 3.6 and 15 X 10(-9) M. The 4-O-met-TPA, alpha PDD and alph PHR were ineffective at 2 X 10(-7) M, the highest concentration tested. Using a 3H-PDBu probe, we demonstrated the presence of specific, high affinity binding sites in intact cultured cells, with a Kd of about 9 X 10(-9) M. Unlabelled TPA, PDD, PDBU and PDBz competed with 3H-PDBu with respective IC50 of 35, 12.5, 150 and 220 X 10(-9) M. High concentrations of PDA, 4-O-met-TPA and alpha PDD slightly inhibited the 3H PDBu binding, whereas alpha PHR did not until 10(-5) M. The correlation that we observed between the relative potencies of the various phorbol derivatives for inhibiting both PDBu binding and cell proliferation, suggests that tumor promoter phorbol esters may induce growth arrest in MCF-7 cells by the mediation of protein kinase C.

Topics: Breast Neoplasms; Cell Division; Cell Line; Dose-Response Relationship, Drug; Female; Humans; Phorbol 12,13-Dibutyrate; Phorbol Esters; Phorbols; Protein Kinase C; Tetradecanoylphorbol Acetate

The tumor promoters mezerein and phorbol myristate acetate, and the phorbol diesters phorbol diacetate, phorbol dibenzoate, and phorbol didecanoate synergistically enhanced the production of lymphotoxin (LT) by phytohemagglutinin-stimulated human peripheral blood or tonsil and adenoid lymphocytes. LT production was elevated 2-20-fold, depending on such parameters as the nature of the promoter and dose, the lectin dose, and the lymphocyte source. The increased LT levels were primarily due to enhanced production of the alpha-light (alpha L) class of LT. The alpha L-class obtained from supernatants from promoter-synergized, lectin-stimulated lymphocyte cultures was compared with the alpha L from lectin-stimulated cultures. They were indistinguishable by molecular sieving on Ultrogel AcA44, were both composed primarily of the alpha 2-subclass as determined by ion-exchange chromatography on DEAE-Sepharose, and were immunologically cross-reactive. Lectin-affinity chromatography on concanavalin A-Sepharose and on lentil-lectin--Sepharose revealed that both alpha L preparations were dominated by components with affinity for these matrices. Affinity chromatography on alkyl sorbents also indicated very similar hydrophobicities. Chromatofocusing of the alpha L preparations demonstrated a comparable pattern of isoelectric points. Thus, the use of these drugs in lectin-stimulated human lymphocyte cultures provides an effective means for significantly increasing the yield of alpha L-LT suitable for biochemical purification and analysis, and biological testing in vitro.

Topics: Carcinogens; Chromatography, Affinity; Chromatography, Ion Exchange; Diterpenes; Humans; In Vitro Techniques; Lymphocytes; Lymphotoxin-alpha; Phorbol Esters; Phorbols; Phytohemagglutinins; Terpenes; Tetradecanoylphorbol Acetate

Topics: Binding Sites; Carcinogens; Cell Differentiation; Cell Line; Cell Membrane; Humans; Leukemia, Myeloid, Acute; Melanoma; Phorbol 12,13-Dibutyrate; Phorbol Esters; Phorbols; Polyamines; Tetradecanoylphorbol Acetate